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PDBsum entry 4n4t
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Transferase/transferase inhibitor
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PDB id
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4n4t
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References listed in PDB file
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Key reference
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Title
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Structure-Based design of 2-Aminopyridine oxazolidinones as potent and selective tankyrase inhibitors.
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Authors
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H.Huang,
A.Guzman-Perez,
L.Acquaviva,
V.Berry,
H.Bregman,
J.Dovey,
H.Gunaydin,
X.Huang,
L.Huang,
D.Saffran,
R.Serafino,
S.Schneider,
C.Wilson,
E.F.Dimauro.
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Ref.
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Acs Med Chem Lett, 2013,
4,
1218-1223.
[DOI no: ]
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PubMed id
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Abstract
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Aberrant activation of the Wnt pathway has been implicated in the development
and formation of many cancers. TNKS inhibition has been shown to antagonize Wnt
signaling via Axin stabilization in APC mutant colon cancer cell lines. We
employed structure-based design to identify a series of 2-aminopyridine
oxazolidinones as potent and selective TNKS inhibitors. These compounds
exhibited good enzyme and cell potency as well as selectivity over other PARP
isoforms. Co-crystal structures of these 2-aminopyridine oxazolidinones
complexed to TNKS reveal an induced-pocket binding mode that does not involve
interactions with the nicotinamide binding pocket. Oral dosing of lead compounds
3 and 4 resulted in significant effects on several Wnt-pathway biomarkers in a
three day DLD-1 mouse tumor PD model.
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